Liver Biochemistry Flashcards
What is the structure of the liver?
4 lobes: right, left, caudate, quadrate
What is the blood supply to the liver?
The hepatic portal vein - brings nutrient-rich venous blood from GI tract (75%) hepatic arteries (25%)
What are the cells of the liver? (6)
hepatocytes endothelial cells hepatic stellate cells cholangiocytes pit cells kupffer cells
What is the function of hepatocytes?
They’re the main cell type in the liver (80%), carry out metabolic liver functions.
CAN REGENERATE
What is the function of liver endothelial cells?
Allow exchange b/w liver and blood via pores & fenestrations in their plasma membrane
What is the function of hepatic stellate cells?
Are storage site for Vitamin A and other lipids
What is the function of cholangiocytes?
They line the bile duct, control bile flow rate and bile pH
What is the function of pit cells?
These are NK cells that protect liver from viruses and tumors (lymphocytes)
What is the function of Kupffer cells? (4)
- Protect liver from gut-derived microbes
- Remove dead cells
- orchestrate immune response
- secrete cytokines
Line the sinusoids. Are specialized macrophages w/good endocytic & phagocytic function and lots of lysosomes
What are the general functions of the liver? (8
- Carbohydrate metabolism
- Lipid metabolism
- Nucleotide biosynthesis
- Protein and amino acid metabolism
- Removal of nitrogen generated by protein & aa metabolism
- Bilirubin metabolism
- Synthesis of blood proteins
- Deactivates/detoxes/biotransforms metabolites and xenobiotics
What specifically does the liver do in carbohydrate metabolism? (6)
Glucostasis (keep blood gluc stable) Glycogen synthesis Glycogenolysis Gluconeogenesis Makes ketones when starving Has Glucose-6-phosphatase to release free gluc to blood
What does the liver do in lipid metabolism? (3)
Biosynthesizes fats
Degrades fats
Regulates FFA Metabolism (making and breaking)
What proteins does the liver synthesize? (7)
Acute phase proteins - CRP - protease inhibitors - alpha-1 antitrypsin - alpha-1 antichymotrypsin albumin IgG apoproteins fibrinogen prothrombin clotting factors V, VII, IX, X
What ways has the liver adapted to facilitate its function? (3)
circulation
structural
cellular
What circulatory adaptations does the liver have to facilitate its function?
It gets blood from enteric circulation and the periphery so it can have first pass for ingested substances
What structural adaptations does the liver have to facilitate its function?
- No basement membrane
- No tight junctions b/w hepatocytes and endothelial cells
- gaps b/w endothelial cells
- pores in endothelial membrane
Basically all this to allow more contact between the liver and blood
What cellular adaptations does the liver have to facilitate its function?
Well-developed plasma membrane and ER, lots of lysosomes and metabolic enzymes
What are the steps of emulsification? (4)
- cholic acid (bile acid) ionizes to give bile salt
- hydrophobic surface of bile salt associates w/TAG, several complexes aggregate to form micelle
- hydrophobic surface of bile salt faces out, allows micelle to interact w/ pancreatic lipase
- hydrophobic action of lipase frees FA’s to break into smaller micelle that’s absorbed through intestinal mucosa
What are the primary bile acids?
- chenodeoxycholic acid
- cholic acid
What are the secondary bile acids?
- deoxycholic acid
- lithocholic acid
What is the difference between primary and secondary bile acids?
Primary - synthesized in liver
Secondary - result from bacterial action in colon. Also have no -OH on carbon 7. They inhibit 7 alpha-hydroxylase!
What are gallstones?
Supersaturated gallbladder bile with cholesterol crystals
What can cause gallstones? (3)
- inefficient bile salt secretion
- inefficient phospholipid secretion
- excess cholesterol secretion
What is the treatment for gallstones? (2)
If too big, cholecystectomy
If small enough, can treat with oral ursodeoxycholic acid, a secondary bile acid that reduces cholesterol secretion, increases biliary cholesterol solubility
How do cholesterol-lowering drugs work? (4 steps)
- bind to bile, causing more of it to be excreted
- bile acid synthesis rate increases by induction of 7alpha-hydroxylase
- liver cholesterol pool depleted, increased uptake of LDL into liver
- lowered plasma cholesterol levels!
What is one cholesterol-lowering drug?
cholestyramine
What are metabolites?
By products of metabolism that your body makes
What are xenobiotics?
medicines/substances taken from ‘outside’
What are the steps of phase 1 reactions of detoxification of xenobiotics?
- Reduction
- Oxidation
- Hydroxylation
- Hydrolysis
What is the purpose of the phase one reaction?
To make a more polar primary metabolite
What catalyzes the phase 1 reaction?
P450 Enzyme (CYP)
What are the steps of the phase 2 reaction?
- Conjugation
- Sulfation
- Methylation
- Glucuronidation
What is the purpose of the phase 2 reaction?
The functional groups are conjugated for safe excretion
What are cytochrome P450 enzymes?
A superfamily of enzymes that play a key role in the metabolism of multiple hydrophobic compounds
What enzyme do CYP enzymes co-localize with?
cytochrome p450 reductase (CYPR)
Why is CYPR important?
It is the rate-limiting enzyme
Which 3 CYP enzymes are the most important?
CYP1, CYP2, CYP3
What are other electron transport systems? (correlation box)
Are in the ER, act as mono-oxidases by utilizing pairs of e- from NADPH to incorporate molecular oxygen into the substrate while reducing a second O2 to water
How do Cytochrome P450 and drugs interact? (correlation box)
Certain drugs increase the rate of reactions, some form a complex with CYP that inhibit them:
drugs that inhibit CYP = increase drug levels of plasma
drugs that stimulate CYP = decrease drug levels in plasma
What is an example of a substance that inhibits CYP?
Citrus juices (esp grapefruit juice)
What is an example of a substance that stimulates CYP?
St. John’s Wort
What sort of changes to the liver do you see in cases of liver disease?
- Normally-leaky basement membrane replaced by dense membrane w/lots of fibrillar collagen
- fenestrations in plasma membrane & space b/w endothelial junctions lost
- Hepatic vascular channels get stiffer, increasing resistance and intra-sinusoidal fluid pressure (portal HTN)
Basically all the normal junk is donked (free exchange of material impaired)
What are liver function tests? (9)
- Albumin
- Transaminases (ALT/AST)
- Alkaline phosphatase
- prothrombin time
- bilirubin (conj/unconj)
- urea
- glucose
- TAG
- cholesterol
Which tests are the best indicators of liver damage?
ALT/AST (ALT more sensitive), they increase in liver disease
Where are ALT/AST found?
Both found in mitochondria, but ALT also found in cytosol
What are the steps of bile acid synthesis?
- conversion of cholesterol to 7 alpha-hydroxycholesterol by 7 alpha-hydroxylase (committed step)
- reduction, hydroxylation, conversion of hydroxyls to alpha becomes 3 alpha, 7alpha-diol
- diverge now - an oxidation of a side chain leads to 3 alpha, 7 alpha, 12, alpha-triol to CHOLIC ACID or conversion of 3 alpha, 7 alpha-diol to CHENODEOXYCHOLIC ACID
- cholic acid converted to cholyl coA, which is converted to taurocholic acid
- cholyl coA becomes glycocholic acid
Which bile acid is most effective?
Taurocholic acid, because the pKa is lower meaning it is more ionizing (better detergent)
